Mechanical stimuli responsive microcarriers for biomedical applications

Abstract

Stimuli responsive micro/nano carriers have been extensively studied as drug delivery systems for controlled and sustained relase of the loaded drug. In the past decade, various kinds of physical stimuli responsive carriers including pH, temperature,etc have been studied for controlled drug delivery in tizes and were applied to various biomedical applications including stimuli responsive and controlled drug release. In chapter 1, recent studies of stimuli responsive micro/nano carriers for biomedical applications are reviewed. Increasing the therapeutic benefits of the delivered drug with minimal side effects and enhanced patient compliance is the main goal of drug delivery research. However, bio-availabilities of clinically delivered free therapeutics are severely restricted due to the hurdles they face in vivo such as various metabolic processes, primarily renal clearance and distribution in non-targeted organs or tissues. In order to overcome these limitations, researchers designed multifunctional drug carriers with ability to encapsulate and controlled release of loaded drug, ability to cross biological barriers and delivery at the targeted site. Stimuli responsive drug carriers are more promising canditates for the on-demand and controlled drug delivery where stimuli of various origins are explored extensively in the past decade such as biological, chemical and physical stimulus. Among these explored stimuli for the responsive drug release, mechanical stimuli is the most easily accessible and universal. The importance of mechanical stimulus and mechanical stimuli responsive systems in controlled and on-demand drug delivery are reviewed here with the scope of this thesis. In chapter 2, We show the preparation of hybrid hollow capsules comprising alternating layers of inorganic colloidal particles and biopolymers via layerby- layer approach followed by freezing-assisted crosslinking of polymer layers. The size of the capsule was controllable by the size of sacrificial cores. These hybrid capsules were mechanically more stable and recover faster than polyelectrolyte capsules, and could be recovered elastically even after large and repetitive deformation up to 98% relative to their original dimensions. Drugs in a wide range of molecular weight up to 70 kDa Mw could be loaded into the hollow hybrid microcapsules and the release of loaded contents from these hybrid capsules could be controlled through the deformation by applying a weak force such as a finger pressing on them. Mechanical stimuli-responsive delivery of model drugs was demonstrated on a monolayer of these hybrid capsules. In chapter 3, we describe Polydimethylsiloxane (PDMS) film with significantly enhanced water permeability and uptake was prepared by incorporating spherical elastic hollow microcapsules (eHMCs) in it. eHMCs were prepared through O/W/O emulsification method. Water permeability and uptake of the film increased significantly in proportion to the amount of embedded eHMCs while minimizing the changes in elastic characteristics and transparency of PDMS. The release rate of loaded water soluble model drug from the eHMC-embedded PDMS film could be controlled by the magnitude of uniaxial mechanical stimulus applied over the film and initial drug loading amount, with negligible release of drug from the film in the absence of external stimulation (during storage). Thus, these biocompatible and elastic composite PDMS films are potentially useful, including as an easily accessible and instantly effective way of controlling hydrophilic drug release using the mechanical stimulus as well as a soft elastomer with enhanced water uptake and permeability. In chapter 4, We shown the fabrication of biocompatible elastic hybrid hollow microspheres (eHHMs) composed of gelatin or HA and hydroxyapatite nanoparticles (HAp NPs), where the microsphere shell cross-linked using a biocrosslinker EDC or divinyl sulfone. Biocompatible synthetic or natural biopolymers based injectable microspheres find wide range of biomedical applications as bulking agents, embolic or drug delivery particles. Among them gelatin and hyaluronic acid (HA) based microspheres are explored well as injectable biomaterials due to its effectiveness, ease of administration and high safety profile. However, it is difficult to tune the size and mechanical properties of these microspheres to a wide range. These eHHMs were elastic enough to recover back to initial dimension after large deformations which makes them injectable. In summary, this thesis describes the feasibility of the mechanical stimuli responsive microcarriers as a promising material for controlled drug delivery applications.